1. Review the concept of dynamic mutation disorders and identify the features common to such disorders. (p.429, 431, 432)
Dynamic mutation disorders result from the expansion of trinucleotide repeats or minisatellite DNA regions located within genes or gene regulatory regions. The number of repeats is unstable and can vary from person to person -- i.e., no fixed number but rather a range of repeats results in risk of developing disease.
Affected individuals with one of the expansion disorders have a sudden increase in the number of copies of the repeat generated during gametogenesis. Large expansions are often associated with altered DNA methylation and loss of gene function. Expansions alters either the expression or the structure of a particular protein and the degree of expansion can increase from generation to generation.
In general, the larger the repeat, the earlier and more severe the onset of disease. Some expansion disorders are characterized by an intermediate pre-mutation expansion where individuals are asymptomatic but can pass on much larger expansions.
Interspersal of sequences different from triplet repeats can stabilize the triplet repeat region by acting as an anchor to prevent polymerase slippage.
2. Review the clinical and molecular genetic characteristics of Fragile X syndrome. (p.433-438)
Fragile X syndrome is the most commone cause of inherited mental retardation in males and the second most common cause of mental retardation after down syndrome. All males with full mutation are affected and have moderate-severe MR hyperactivity, autistic features, ADD, narrow face with prominent forehead, jaw and ear macroorchidism, and folate-sensitive fragile site at Xq27.3. Approximately 40-50% of females with full mutation are affected but have milder manifestations, probably because of x-inactivation protection.
FMR1 gene coding for FMRP is affected. FMRP is normally concentrated in neurons and is associated with polyribosomes, suggesting a translation role in formting translation-competent mRNP (ribonucleoprotein). FMR1 gene contains unstable repeat sequence of CGG.
Status
Number of Repeats
Comment
Normal
5-45
Normal Individual (Average 30
Above Normal
45-60
Limited Instability (AGG Interspersion)
Premutation
60-200
Transmission Instability
Full Mutation
230-1,000+
Affected
When more than 230 repeats, the 5'end of the FMR1 gene becomes hypermethylated and transcription is shut off, resulting in deficiency of FMR1 mRNA and FMRP. Expanding repeate is highly unstable during mitosis and can result in extensive repeat number mosaicism depending on different tissue types.
Risk of having affected offspring depends on the sex of transmitting parent and number of repeats. Mothers have a high risk of expansion to full mutation in offspring compared to fathers and greater number of repeats in maternal meiosis increases the risk of full mutation. Contraction of maternal premutation to a normal length or of a full mutation to a premutation are rare.
Carriers are often regarded as being unaffected but can actually present with:
(1) Mild cognitive and/or behavioral deficits on fragile x spectrum
(2) Premature ovarian failure
(3) Fragile X-associated tremor/ataxia syndrome affecting older adult carriers
3. Review the clinical molecular genetic characteristics of Huntington disease. (p.433, 439-441)
Huntington's disease is a dominantly inherited progressive brain disorder resulting in mental and physical degeneration and death within 15-20 years of onset.
Caused by the expansion of CAG repeats in the Huntingtin gene, resulting in a polyglutaminated Huntingtin protein. Polyglutaminated Huntingtin aggregatesin brain cell nuclei and binds to huntingtin-associated protein in the brain, resulting in atrophy of the basal ganglia and dialation of the lateral ventricle. Increasing number of CAG repeats increases the risk of Hungtington's disease (36+ repeats).
4. Review the concept of uniparental disomy, its various mechanisms of origine, and its relationship to genomic imprinting in the causation of certain genetic disease. (p.442-450)
Uniparental Disomy (UPD) results when a baby inherits two copies of a chromosome pair from one parent and no copy from the other parent (can be maternal or paternal UPD). UPD can result in rare recessive disorders or developmental problems due to effects of imprinting but can also be asymptomatic.
UPD results in non-disjunction either in meiosis I or II. This results ina trisomy situation at fertilization; the zygote then attempts to do a trisomy rescue by kicking out one of the chromosomes but randomly selects which chromosome. Thus, there is a 2/3 chance of successful rescue and no problems but 1/3 chance of resulting in UPD. Alternatively, UPD can result in duplication from a monosomic zygote via monosomic rescue or fertilization of a gamate with two copies of a chromosome by a gamate with no copies of a chromosome (gamate complementation). All these mechanisms require two consecutive mistakes.
Uniparental Heterodisomy is a trisomy rescue after error in meiosis I with inheritance of two homologous chromosomes from one parent but with different genetic material on the actual chromosomes. Uniparental Isodisomy is a trisomy rescue after error in meiosis II with inheritance of two identical copies of the chromosome from one parent.
Because both copies of the chromosome are from one parent, they are both genetically imprinted to express that parent's contribution and can result in errors because of the missing genetic imprinting contribution by the other parent.
5. Review the concept of genomic imprinting and the role it plays in normal human development and in genetic disese. (p.450-455)
Genomic imporiting is the epigenetic marking of a gene based on its parental origin by DNA methylation and/or histone deacetylation. This results in monoallelic expression despite an equal contribution by both parents to the genetic content of their progeny. Genetic imprinting is established in embryonic development: Egg and sperm contain pre-existing imprinting that is retained following fertilization and in somatic cells; However, when germ line cells make new gamates, the imprinting is reset to a gender specific imprint.
UBE3A in angelman syndrome and SNRPN in prader-willi syndrome are affected by genomic imprinting disorders.
6. Demonstrate the roles of genetic imprinting and uniparental disomy in the pathogenesis of Prader Willi (PWS) and Angelman syndromes (AS). (p.456, 458, 459, 460)
In Gobbly-Goop
Prader-Willi Syndrome (PWS) is caused by errors in the PWS/PS region of parental chromosome 15. 70% have ad deletion of the PWS region in the paternal chromosome, 25% have maternal UPD of chromosome 15, 5% have a mutation in a gene controling imprinting, and very rarely, some have a chromosome abnormality including the PWS region.
In English
You can have PWS if your paternal PWS region on chromosome 15 is messed up somehow and you can't make the SNRPN protein. You can have:
(1) a deletion on the paternal PWS region on chromosome 15
(2) maternal UPD of chromosome 15, meaning you don't have the paternal chromosome 15 at all, including the PWS region
(3) Error in genomic imprinting of PWS region such that the active gene on the paternal chromosome 15 is "off" instead of "on"
In Gobbly-Goop
Angelman Syndrome (AS) is similar to PWS, being caused by errors in the AS region of chromosome 15. 70% have a deletion of the AS region on the maternal chromosome 15, 7% have paternal UPD for chromosome 15, 3% have an imprinting defect, 11% have a mutated UBE3A gene, 1% have a chromosome rearrangement involving the PWS/PS region, and 11% have an unknown genetic cause.
In English
You can have AS if your maternal PS region on chromosome 15 is messed up somehow can you make the UBE3A protein. You can have:
(1) a deletion on the maternal AS region on chromosome 15
(2) paternal UPD of chromosome 15, meaning you don't have the maternal chromosome 15 at all, including the AS region
(3) Error in genomic imprinting of AS region such that the active gene on the maternal chromosome 15 is "off" instead of "on"
Objectives
1. Review the concept of dynamic mutation disorders and identify the features common to such disorders. (p.429, 431, 432)
Dynamic mutation disorders result from the expansion of trinucleotide repeats or minisatellite DNA regions located within genes or gene regulatory regions. The number of repeats is unstable and can vary from person to person -- i.e., no fixed number but rather a range of repeats results in risk of developing disease.
Affected individuals with one of the expansion disorders have a sudden increase in the number of copies of the repeat generated during gametogenesis. Large expansions are often associated with altered DNA methylation and loss of gene function. Expansions alters either the expression or the structure of a particular protein and the degree of expansion can increase from generation to generation.
In general, the larger the repeat, the earlier and more severe the onset of disease. Some expansion disorders are characterized by an intermediate pre-mutation expansion where individuals are asymptomatic but can pass on much larger expansions.
Interspersal of sequences different from triplet repeats can stabilize the triplet repeat region by acting as an anchor to prevent polymerase slippage.
2. Review the clinical and molecular genetic characteristics of Fragile X syndrome. (p.433-438)
Fragile X syndrome is the most commone cause of inherited mental retardation in males and the second most common cause of mental retardation after down syndrome. All males with full mutation are affected and have moderate-severe MR hyperactivity, autistic features, ADD, narrow face with prominent forehead, jaw and ear macroorchidism, and folate-sensitive fragile site at Xq27.3. Approximately 40-50% of females with full mutation are affected but have milder manifestations, probably because of x-inactivation protection.
FMR1 gene coding for FMRP is affected. FMRP is normally concentrated in neurons and is associated with polyribosomes, suggesting a translation role in formting translation-competent mRNP (ribonucleoprotein). FMR1 gene contains unstable repeat sequence of CGG.
When more than 230 repeats, the 5'end of the FMR1 gene becomes hypermethylated and transcription is shut off, resulting in deficiency of FMR1 mRNA and FMRP. Expanding repeate is highly unstable during mitosis and can result in extensive repeat number mosaicism depending on different tissue types.
Risk of having affected offspring depends on the sex of transmitting parent and number of repeats. Mothers have a high risk of expansion to full mutation in offspring compared to fathers and greater number of repeats in maternal meiosis increases the risk of full mutation. Contraction of maternal premutation to a normal length or of a full mutation to a premutation are rare.
Carriers are often regarded as being unaffected but can actually present with:
(1) Mild cognitive and/or behavioral deficits on fragile x spectrum
(2) Premature ovarian failure
(3) Fragile X-associated tremor/ataxia syndrome affecting older adult carriers
3. Review the clinical molecular genetic characteristics of Huntington disease. (p.433, 439-441)
Huntington's disease is a dominantly inherited progressive brain disorder resulting in mental and physical degeneration and death within 15-20 years of onset.
Caused by the expansion of CAG repeats in the Huntingtin gene, resulting in a polyglutaminated Huntingtin protein. Polyglutaminated Huntingtin aggregatesin brain cell nuclei and binds to huntingtin-associated protein in the brain, resulting in atrophy of the basal ganglia and dialation of the lateral ventricle. Increasing number of CAG repeats increases the risk of Hungtington's disease (36+ repeats).
4. Review the concept of uniparental disomy, its various mechanisms of origine, and its relationship to genomic imprinting in the causation of certain genetic disease. (p.442-450)
Uniparental Disomy (UPD) results when a baby inherits two copies of a chromosome pair from one parent and no copy from the other parent (can be maternal or paternal UPD). UPD can result in rare recessive disorders or developmental problems due to effects of imprinting but can also be asymptomatic.
UPD results in non-disjunction either in meiosis I or II. This results ina trisomy situation at fertilization; the zygote then attempts to do a trisomy rescue by kicking out one of the chromosomes but randomly selects which chromosome. Thus, there is a 2/3 chance of successful rescue and no problems but 1/3 chance of resulting in UPD. Alternatively, UPD can result in duplication from a monosomic zygote via monosomic rescue or fertilization of a gamate with two copies of a chromosome by a gamate with no copies of a chromosome (gamate complementation). All these mechanisms require two consecutive mistakes.
Uniparental Heterodisomy is a trisomy rescue after error in meiosis I with inheritance of two homologous chromosomes from one parent but with different genetic material on the actual chromosomes. Uniparental Isodisomy is a trisomy rescue after error in meiosis II with inheritance of two identical copies of the chromosome from one parent.
Because both copies of the chromosome are from one parent, they are both genetically imprinted to express that parent's contribution and can result in errors because of the missing genetic imprinting contribution by the other parent.
5. Review the concept of genomic imprinting and the role it plays in normal human development and in genetic disese. (p.450-455)
Genomic imporiting is the epigenetic marking of a gene based on its parental origin by DNA methylation and/or histone deacetylation. This results in monoallelic expression despite an equal contribution by both parents to the genetic content of their progeny. Genetic imprinting is established in embryonic development: Egg and sperm contain pre-existing imprinting that is retained following fertilization and in somatic cells; However, when germ line cells make new gamates, the imprinting is reset to a gender specific imprint.
UBE3A in angelman syndrome and SNRPN in prader-willi syndrome are affected by genomic imprinting disorders.
6. Demonstrate the roles of genetic imprinting and uniparental disomy in the pathogenesis of Prader Willi (PWS) and Angelman syndromes (AS). (p.456, 458, 459, 460)
In Gobbly-Goop
Prader-Willi Syndrome (PWS) is caused by errors in the PWS/PS region of parental chromosome 15. 70% have ad deletion of the PWS region in the paternal chromosome, 25% have maternal UPD of chromosome 15, 5% have a mutation in a gene controling imprinting, and very rarely, some have a chromosome abnormality including the PWS region.
In English
You can have PWS if your paternal PWS region on chromosome 15 is messed up somehow and you can't make the SNRPN protein. You can have:
(1) a deletion on the paternal PWS region on chromosome 15
(2) maternal UPD of chromosome 15, meaning you don't have the paternal chromosome 15 at all, including the PWS region
(3) Error in genomic imprinting of PWS region such that the active gene on the paternal chromosome 15 is "off" instead of "on"
In Gobbly-Goop
Angelman Syndrome (AS) is similar to PWS, being caused by errors in the AS region of chromosome 15. 70% have a deletion of the AS region on the maternal chromosome 15, 7% have paternal UPD for chromosome 15, 3% have an imprinting defect, 11% have a mutated UBE3A gene, 1% have a chromosome rearrangement involving the PWS/PS region, and 11% have an unknown genetic cause.
In English
You can have AS if your maternal PS region on chromosome 15 is messed up somehow can you make the UBE3A protein. You can have:
(1) a deletion on the maternal AS region on chromosome 15
(2) paternal UPD of chromosome 15, meaning you don't have the maternal chromosome 15 at all, including the AS region
(3) Error in genomic imprinting of AS region such that the active gene on the maternal chromosome 15 is "off" instead of "on"